The NAD-dependent histone deacetylase Sir2 plays important roles in regulating gene silencing in yeast and can extend the life span of several model organisms. The mammalian Sir2 ortholog SirT1 has been implicated in the regulation of key factors involved in growth arrest and apoptosis, including p53, NF-?b and Forkhead. We have found that E2F1 regulates SirT1 expression at the promoter level. Furthermore, SirT1 binds to E2F1 and inhibits E2F1 transcriptional and apoptosis functions, forming an apparent negative feedback loop. Knockdown of SirT1 increases E2F1 transcriptional and apoptosis activities. DNA damage by etoposide causes E2F1-dependent induction of SirT1, and knockdown of SirT1 increases sensitivity to etoposide. These results reveal a mutual regulation between E2F1 and SirT1 that affects cellular sensitivity to DNA damage. We also found that phosphorylation of SirT1 on multiple sites may regulate its deacetylase activity. We hypothesize that SirT1 expression and activity are regulated by oncogenic and Stress signals, contributing to tumor cell survival and treatment resistance. We propose the following experiments to investigate the role of SirT1 in tumor cells, and to evaluate the potential of targeting SirT1 in cancer therapy. (1) Investigate the mutual regulation of E2F1 and SirT1. (2) Determine the effects of SirT1 on tumor formation and treatment response. (3) Investigate the regulation of SirT1 by phosphorylation. (4) Investigate the role of SirT1 in ribosomal stress response. These experiments should lead to a better understanding of the role of SirT1 and may identify novel therapeutic targets for cancer.